Target Research 2012 (4 of 4) by Muscular Dystrophy UK

Target Research Issue 4 of 4 2012

See the big picture

Your questions answered A must read

Exercise for people with neuromuscular conditions An update into the exercise studies we funded from the scientists who led the research teams.

HFEA launches mitochondrial disease consultation Make your voice heard Also insideâ&#x20AC;Ś read about all the latest research and clinical trial news from the UK and around the world

Glossary This glossary is intended to help with some of the scientific and technical terms used in this magazine. Words that are in the glossary are highlighted in italics in the text. Adeno-associated viruses (AAV) – a small virus which infects humans and some other primate species. AAV is not currently known to cause disease and consequently the virus causes a very mild immune response. These features make AAV a very attractive vehicle for delivering gene therapy into cells. Animal model – a laboratory animal such as a mouse or rat that is useful for medical research because it has specific characteristics that resemble a human disease or disorder. Biomarker - a biological substance found in blood, urine or other parts of the body that can be used as an indicator of health or disease. A biomarker may be used to help clinicians diagnose a condition and monitor how it is progressing, but can also be used to see how well the body responds to a treatment. Biopsy - the removal of a sample of tissue (such as muscle) from the body. The tissue can then be examined under a microscope. Cell - the structural and functional unit of all known living organisms. They are often called the building bricks of life. DNA – (deoxyribonucleic acid) is the molecule that contains the genetic instructions for the functioning of all known living organisms. DNA is divided into segments called genes. Dystrophin - the protein missing in people who have Duchenne muscular dystrophy and reduced in those who have Becker muscular dystrophy. The dystrophin protein normally sits in the membrane that surrounds muscle fibres like a skin, and protects the membrane from damage during muscle contraction. Without dystrophin the muscle fibre membranes become damaged and eventually the muscle fibres die. Exon – genes are divided into regions called exons and introns. Exons are the sections of DNA that code for the protein and are interspersed with introns, which are also sometimes called “junk DNA”. Exon skipping – a potential therapy currently in clinical trial for Duchenne muscular dystrophy. It involves ‘molecular patches’ or ‘antisense oligonucleotides’ which mask a portion (exon) of a gene and causes the body to ignore or skip-over that part of the gene. This restores production of the dystrophin protein, albeit with a piece missing in the middle. Gene - genes are made of DNA and each carries instructions for the production of a specific protein. Genes usually come in pairs, one inherited from each parent. They are passed on from one generation to the next, and are the basic units of inheritance. Any alterations in genes (mutations) can cause inherited disorders. Immune response - the body’s response to ‘foreign’ material, such as bacteria or a virus.

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In-vitro fertilisation (IVF) – a process by which the egg is fertilised by sperm outside the womb. Magnetic resonance imaging (MRI) – a noninvasive body imaging procedure that uses powerful magnets and radio waves to construct pictures of the internal structures of the body. Molecular patch – a short piece of genetic material (DNA or RNA) which can bind to a specific gene and change how the code is read. They can be used to mask errors in the genetic code, this is known as exon skipping and is in clinical trial for Duchenne muscular dystrophy. Certain types are also being investigated in the laboratory for their ability to completely switch off genes. Also called antisense oligonucleotides. Mutation – the alteration of a gene. Mutations can be passed on from generation to generation. Non-sense mutation – a change in the DNA which causes a premature stop signal to occur in a gene. When this happens protein is either not produced at all or does not function properly. Phase 1 clinical trial – a small study designed to assess the safety of a new treatment and how well it’s tolerated, often using healthy volunteers. Phase 2 clinical trial – a study to test the effectiveness of a treatment on a larger number of patients. Participants are usually divided into groups to receive different doses or a placebo. Placebo - an inactive substance designed to resemble the drug being tested. It is used to rule out any benefits a drug might exhibit because the recipients believe they are taking it. Protein – molecules required for the structure, function, and regulation of the body’s cells, tissues, and organs. Our bodies contain millions of different proteins, each with unique functions. The instructions for their construction are contained in our genes. Randomised controlled trial - a clinical trial where treatments and placebo are allocated randomly to participants rather than by conscious decisions of clinicians or patients. Six minute walk test - a standardised way of measuring a patients mobility. It involves measuring how far a person can walk in six minutes. Stem cells – cells that have not yet specialised to form a particular cell type, and can become other types of cell such as muscle cells. They are present in embryos (embryonic stem cells) and in small numbers in many adult organs and tissues, including muscle. Utrophin – a very similar protein to dystrophin. Low levels of utrophin are present in everyone - including people with Duchenne muscular dystrophy - but in insufficient amounts to compensate for the loss of dystrophin.

The Muscular Dystrophy Campaign is the leading UK charity fighting musclewasting conditions. We are dedicated to beating muscular dystrophy and related neuromuscular conditions by finding treatments and cures and to improving the lives of everyone affected by them. The Muscular Dystrophy Campaign’s medical research programme has an international reputation for excellence, investing more than £1m each year, which includes more than 25 live projects taking place at any one time. Our information, care and support services, support networks and advocacy programmes support more than 5,000 families across the UK each year. We have awarded more than 6,000 grants totalling more than £6m towards specialist equipment, such as powered wheelchairs. Disclaimer While every effort has been made to ensure the information contained within Target Research is accurate, the Muscular Dystrophy Campaign accepts no responsibility or liability where errors or omissions are made. The views expressed in this magazine are not necessarily those of the charity. ISSN 1663-4538 Muscular Dystrophy Campaign 61 Southwark Street London SE1 0HL t: 020 7803 2862 e: info@muscular-dystrophy.org w: www.muscular-dystrophy.org

Registered Charity No. 205395 and Registered Scottish Charity No. SC039445 Printed on PEFC paper, produced at a mill that is certified with the ISO14001 environmental management standard Enclosed into a bio-degradeable polybag

Welcome to Target Research Before I tell you about the exciting stories in this issue of Target Research, I should introduce myself. I’m Neil Bennett, and I’ll be the research communications officer whilst Kristina is on maternity leave.

Welcome

Our main feature in this issue is an article about magnetic resonance imaging (or MRI). We talk to a clinician and a researcher who use the technique to diagnose neuromuscular diseases and to support clinical trials. They answer your questions about the technique and explain why you might have an MRI and what it can tell clinicians. We also have an article highlighting two Muscular Dystrophy Campaign-funded clinical studies about the importance of exercise for people with neuromuscular diseases and the usual round-up of research and clinical trials news from the UK and around the world. We cover the HFEA consultation into IVF techniques with the potential to stop mitochondrial myopathy being passed from mother to child and report the latest encouraging news from the ongoing exon skipping clinical trials. I do hope you enjoy my first issue of Target Research. If you have any questions you’d like to see answered, or articles you’d like to see in the magazine please get in touch!

Neil Bennett Editor, Target Research t: 020 7803 4813 e: n.bennett@muscular-dystrophy.org tw: @NBennettMDC

Contents 4 Magnetic Resonance imaging – what do the scans show and how are the pictures generated? 7 Mitochondrial disease consultation – make your voice heard. Dr Marita Pohlschmidt, Director of Research 8 Research and clinical trials – news from the UK and around the world 14 Exercise studies – an update from the scientists who led the research teams 15 Ask a scientist – your questions answered by experts in the field

MRI

Magnetic Resonance Imaging

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5 Magnetic resonance imaging (MRI) is often used to help clinicians diagnose conditions such as muscular dystrophy or related neuromuscular conditions. Whilst many people with one of these conditions will have had an MRI scan, the way it works is often thought of as something of a mystery. In this article we talk to Dr Tracey Willis and Dr Kieran Hollingsworth. Tracey is a former Muscular Dystrophy Campaign-funded clinical fellow and was part of the muscle team at Newcastle University. Within her fellowship she completed a study that investigated the natural progression of a rare form of limb-girdle muscular dystrophy (LGMD), LGMD2I, using MRI. She is now a Consultant Paediatric Neurologist with a specialty interest in neuromuscular disorders and runs the muscle clinic at the Robert Jones and Agnes Hunt Orthopaedic Hospital. Dr Kieran Hollingsworth is a Lecturer in MRI physics at Newcastle University who worked in collaboration with Tracey on the MRI studies at Newcastle University and continues to work on other projects in muscle disease. They will answer your questions and explain why you might have an MRI scan, how it works, and how clinicians use it to diagnose muscle disease and to help measure the effects of potential new drugs in clinical trials. MRI in the muscle clinic MRI is a non-invasive technique which can produce images of the inside of our bodies. Unlike an X-ray which only shows our bones, MRI images can show the structure of different types of tissue such as muscle, fat, and bone. MRI helps clinicians in making the right diagnosis and it can be informative in a number of ways. Different forms of muscular dystrophies can be distinguished by the different muscles which are involved. MRI is routinely used in the clinics to better visualise which muscles are affected in an individual. Over the last five – ten years our understanding about which muscles are involved in different conditions has increased. We can therefore look at which muscles are affected and how severely to help us make a more accurate diagnosis. Since MRI shows where fat has replaced the skeletal muscle it can help us to decide which muscle would be best to take a biopsy from. We do not want to take a muscle biopsy from a muscle

that has been mainly replaced by fatty tissue as it is muscle tissue we need to analyse to try to determine the cause of the problem. Therefore MRI is also used as a guide by surgeons when performing a muscle biopsy. An MRI scan usually takes about an hour and the patient lies on their back on a moveable table which slides inside the cylinder shaped scanner.

“Most people who’ve had an MRI will remember being moved into a tunnel. Around the tunnel is a magnet that is 100,000 times stronger than the earth’s magnetic field. “

which is like a radio aerial – to detect these radiowaves, just like the film in your camera detects light. Just like the different coloured items in the photograph reflect light differently, different tissues (fat and muscle, for example) release radiowaves differently. Like the film in a camera, MRI can detect these differences giving us an image of the inside of the body that can show us the different kinds of tissue (such as healthy muscle, bone and fat). As an example, these images can show us which muscles are involved in a muscle disease and show how much fat and connective tissue has replaced the skeletal muscle in patients with muscular dystrophy.

This temporarily alters the properties of some of the molecules that make up our body and the scanner can exploit these changes using radiowaves and computers to produce images of the inside of our body. When we suspect a patient may have, for example, a muscular dystrophy, we usually scan the leg from the patient’s hips to the ankles. On the MRI scan we see a cross section through the legs showing the bone, muscles and fat underneath the skin. Normally, the muscles appear black (or dark) with a slightly brighter outline indicating the borders of the muscles while the fat under the skin and the bone marrow is bright. In an individual affected by mild muscle disease the muscles may have a slightly moth eaten appearance and they can appear white (or pale) on the images when they have been replaced by fat and connective tissue. How does MRI work? Imagine taking a photograph in the dark: the flash on the camera fires light at the subject. Different colours reflect light differently and the camera is able to detect these differences using lightsensitive film (or a computer chip) to make a picture of the subject. MRI is very similar, but takes pictures of the inside of our bodies using radiowaves to build the picture instead of light. To create the picture, the MRI scanner sends radiowaves (the flash, in the photograph) into the body which the different tissues in the body absorb and then release (the reflection of the light, in the photograph). The MRI scanner then uses a receiver coil –

MRI in research In the field of neuromuscular research, MRI is becoming more commonplace. It is used in three main ways: Increasing accuracy of diagnosis MRI is already routinely used in the clinic as a reliable diagnostic tool. It is a fast and non-invasive method for clinicians to get an overall picture of the state of the muscles. For most muscular dystrophies and related neuromuscular conditions clinicians have a good idea of what the muscles look like in an MRI image, but for other rarer, complex or extremely variable conditions research is still ongoing. These studies include patients with a confirmed diagnosis to investigate what their muscles look like in an MRI image and the results are compared to other tests that measure muscle strength and function. This knowledge can subsequently help clinicians to provide a faster and more accurate diagnosis. leading the way forward

6 Understanding the progression of muscle disease Understanding how neuromuscular conditions progress is vital for clinicians to give patients more accurate prognostic information. Knowing what is around the corner enables individuals to better plan for the future and ensure that their requirements are met. These studies that observe patients over a long time and collect clinical data are called natural history studies. MRI is a useful tool for collecting natural history data because it is non-invasive and can be used repeatedly. These studies provide researchers with a clear picture of how the different muscles waste away and also provide information about the variability between different individuals and family members.

Are MRI scans safe? Just like the camera needing a flash to take a photo in the dark, most techniques which produce images of the inside of our body need to put energy of some sort into the body. This energy can take many forms - for the camera, light energy; for X-ray pictures or CT scans, X-rays; and for ultrasound, sound waves. MRI uses radiowaves. This means it’s very safe and can be repeated several times if we want to see how a person’s body changes over time. Because the radiowaves used in MRI can make metal and tissues heat up, it is important to let your clinician know if you have any implants or metal fragments in your body. These might include: • surgical clips • a history of metal fragments in your eyes • pacemakers or defibrillators • inner ear implants • infusion pumps • clips, shunts, or stents • intrauterine contraceptive devices • metal fragments anywhere in your body • gun/shrapnel wounds. We also need to know if you have any body piercings, tattoos or transdermal patches. This list isn’t exhaustive, and if in doubt it’s always best to ask your treating physician.

The MR images show a cross-section through the thigh (upper leg) of 5 different people. The images are dark where there is no fat (healthy muscle) and bright where there is fat: the fat under the skin and inside the leg bones is also bright. The person on the left doesn’t have any muscle disease, and the other four have limb girdle muscular dystrophy 2I with more and more muscle tissue being replaced by fat. Using these pictures, we can measure exactly how much fat there is in each muscle and find out how this changes over time.

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Measuring the benefit of potential treatments in clinical trials A clinical trial is a study that assesses the benefit of a potential drug or treatment in a controlled environment. The methods used to assess the benefit are called outcome measures. These include how far somebody can walk in a certain time - a six minute walk test is widely used in ongoing clinical trials that test several potential treatments for Duchenne muscular dystrophy - and tests that measure muscle strength and also quality of life indicators. Often, gauging the amount of muscle damage in trial participants is also important. Currently muscle biopsies are used to measure this, but this is invasive, it is difficult to use repeatedly on an individual that has a muscle wasting disease and it only captures a small snapshot of what is happening in muscles elsewhere in the body. MRI is non-invasive, it can be used repeatedly and it can assess any muscle in the body. It can be used to understand how well the muscles are responding to a treatment by assessing the amount muscle damage and the amount of muscle that has

7 been replaced by fat or connective tissue. It has been demonstrated to be a sensitive method to see change, with the amount of muscle loss on the MRI scans being linked to muscle strength and functional testing to give an accurate measure of muscle health. Importantly, using special programs, we can compare the results between different MRI scanners in different countries, allowing all participants in international trials to be compared. How will MRI change in the future? Thanks to modern MRI scanners and stronger magnets, we are able to take images of the inside of the body with greater clarity and accuracy than ever before. It is still possible to make MRI examinations faster and at the moment at Newcastle University we are developing new techniques which will speed up MRI examinations for people with muscular dystrophy:

“the aim is to allow us to scan in 8 minutes what would take 30 minutes today.” It is possible to use MRI to track muscle loss by measuring exactly how much fat and connective tissue has infiltrated into the affected muscle - but today’s technology can only produce an image of a muscle as a whole. Looking further into the future, researchers would really like to know what is happening to the cells of the damaged muscles. Ideally we would like to make chemicals which could be injected into patients and be attracted to particular parts of the cells that we are trying to repair. If these chemicals then showed up in the MRI image, it would let us examine the structure of individual cells and the success of potential treatments. This is very challenging research, since the chemicals have to be present in sufficient amount to appear on an MRI image, and also safe to inject. At the

moment, chemicals that can be used in this way are not ready for use in humans. Current MRI technology is not only used for muscles that help us move. It’s now possible to track muscle loss and to measure exactly how much fat has infiltrated into the affected muscle – this can show how advanced the disease is and how it is progressing. We can make detailed examinations of abnormalities of the heart – using special programs to measure the heart wall and construct a movie of how the heart walls contract and twist during a heartbeat – which can show exactly how the structure and function of the heart is changing in people with muscular dystrophy over time. Presently, these MRI research techniques are used in major research hospitals, but in the future we can expect them to become more widely used in routine examinations. Could MRI replace the muscle biopsy? In some cases MRI can replace muscle biopsy. If a particular pattern of muscle involvement is seen on the MRI and this, together with the patient’s medical history and an examination suggests a particular condition then genetic tests could be carried out directly. Only if the tests were negative might a muscle biopsy be required. In the immediate future, it is unlikely that MRI will replace all muscle biopsies, because the diagnosis of many neuromuscular conditions depends on a combination of the symptoms, medical examination, MRI images, and muscle biopsy. For MRI to completely replace muscle biopsies, further work and clinical studies would be needed to link the abnormalities seen on muscle biopsies and those seen on MRI and to link these abnormalities with specific conditions.

Mitochondrial myopathies – can we break the cycle? The charity has been funding research into an IVF technique that could prevent women affected by mitochondrial disease passing the condition on to future children. This is wonderful news because it is notoriously difficult for clinicians to provide parents with genetic counselling and predict how the condition will progress. Developing a treatment that avoids this dilemma and gives parents the opportunity to have children free of devastating diseases can only be described as progress. But those of you that have followed the media must feel differently. Headlines such as ‘Three Parent Child’ suggest we are entering Frankenstein’s world rather than trying to find a way to help families have healthy children. The media is having a field day and therefore it is all the more important to understand the facts behind this. True, the future child will have DNA from three different sources. But the vast majority of the genes (99.9%) that determine character and physical appearance will come from the parents. Only the mitochondria (0.1%) are of donor origin. True also that the technique can only be used to treat these conditions and cannot be used to generally modify genes located on chromosomes in the nucleus. The current law prevents the technique being tested in clinical trial and it needs to be changed for the technique to be taken forward into clinical practice. The HFEA has launched a consultation on behalf of the government to seek public opinion. The families are behind this technique – they can balance risks against benefits. We have to make sure that their voices are heard. We have to encourage a factual debate and we have to ensure that facts override scaremongering. Please take part in the consultation and give parents the right in the future to choose this technique to have healthy children. Dr Marita Pohlschmidt Director of Research, Muscular Dystrophy Campaign. leading the way forward

of Kennedy’s disease – also known as spinal bulbar muscular atrophy.

Research

news

Using a virus to deliver molecular patches Researchers from Prof Kay Davies’ group have taken a step towards finding a technique with the potential to deliver molecular patches to more muscles of the body, including the heart. The scientist used a type of virus called an Adeno-associated virus which has never been shown to cause disease in humans but has the ability to infect muscle cells. The virus used in this study was modified to carry the genetic blueprint of the molecular patches. Scientists believed this virus would infect muscle cells and produce high levels of the molecular patches where they were most needed. The team used a mouse model which develops symptoms similar to Duchenne muscular dystrophy at an early age. Following a single injection of the virus the researchers found the same levels of dystrophin in the muscles as would be seen in healthy mice. Muscle fibres in treated mice were also restored to comparable condition to healthy mice and the change in the overall condition of the mice was significant: in mice injected with the virus carrying the genetic blueprint for the molecular patches muscle strength increased, curvature of the spine was reduced and the mice survived for about one year before symptoms returned. Most importantly, levels of dystrophin in the heart were especially high – something, the researchers say,

which has challenged some methods of molecular patch delivery. One disadvantage of the technique is that immune responses against Adenoassociated virus have been detected in humans which could prevent the virus delivery system from working. However, research is currently underway to investigate the use of immune-suppression (drugs which stop the immune system working properly) to stop the body making an immune response to the virus. In the study the mice received only a single injection whose effects lasted almost one year. If this delivery method was successful in clinical trials, it might reduce the number of injections required to deliver molecular patches. However, like all other exon-skipping technology, this potential treatment would not cure Duchenne muscular dystrophy – but would reduce the severity of symptoms to a level similar to that seen in Becker muscular dystrophy. London myology forum 2012 In July, the Muscular Dystrophy Campaign research team attended the 9th annual London myology forum – an afternoon conference for scientists working on muscle disease in and around London, which is part-funded by the Muscular Dystrophy Campaign.

My particular highlight was a talk by Prof Linda Greensmith, from UCL, whose laboratory has been testing a drug called arimoclomol in a mouse model

When cells become stressed they turn on something called the heatshock response. This can reduce the damage to proteins which stress can cause. Arimoclomol has been designed to boost this heat shock response inside cells. The researchers found that mice treated with the drug showed improved muscle force and nerve cell survival – raising the possibility of a potential future treatment for Kennedy disease. In cells grown in the laboratory, the same drug also shows the potential to prevent the formation of clumps of protein similar to those seen in inclusion body myositis (IBM). Prof Mike Hanna (also from UCL) is now organising a clinical trial in the USA to test whether the drug may have the potential to treat IBM. This meeting was my first chance to talk to the scientists who investigate muscle disease. I found the afternoon very interesting, and was impressed by the range of research going on in the muscle disease field – from basic science to clinical trials – and how this research is leading scientists towards treatments for muscle diseases. Shaken not stirred: molecular patch cocktail advances exon skipping As a so-called “personal medicine”, exon skipping technology requires the development of a different molecular patch for each of the different mutations found in the dystrophin gene. Every molecular patch requires successful testing for safety and efficiency in clinical trial before it can be transferred into clinical practice. If it were possible to develop a mixture of molecular patches with the potential to treat a greater number of boys than one molecular patch, it could reduce the resources and time needed to bring this potential treatment to more boys, more quickly. A team of scientists from America, France and Japan investigated whether ten molecular patches could be used to skip a large part of the dystrophin gene - from exon 45 to exon 55 - at the same time. First, the scientists tested each individual molecular patch separately

9 in muscle cells lacking the dystrophin protein grown in the laboratory. Successful exon skipping was observed for each patch. The ten molecular patches were then combined into a cocktail, and added to the muscle cells. The muscle cells then produced a shorter form of the dystrophin protein. Following these encouraging results, the technology was tested in a mouse model of Duchenne muscular dystrophy. Injection of the molecular patch cocktail into the bloodstream restored dystrophin production in skeletal muscles to up to 15% of the level found in healthy mice. However, restoration of dystrophin production in the heart was less efficient, with around 2% of the levels seen in healthy mice. This study has demonstrated that a cocktail of up to 10 molecular patches can be used at the same time. Treatment of mice with the molecular patch cocktail restored dystrophin production in all the skeletal muscles examined. The cocktail for exons 45-55 of dystrophin covers the area where most deletion mutations are found. Although further development will be required before it could be tested in clinical trials, it may have the potential to treat 40% of boys with Duchenne muscular dystrophy. It must be noted that like skipping an individual exon, skipping 10 exons at the same time would not represent a cure for Duchenne muscular dystrophy. However, it could reduce the severity

of symptoms to a level similar to those seen in Becker muscular dystrophy. The researchers mention that individuals with Becker muscular dystrophy as a result of a deletion of exons 45-55 generally experience only very mild symptoms. This is encouraging, because it might mean that the resulting shorter dystrophin protein has retained most of its function and that skipping exons 4555 could develop into a very efficient treatment for Duchenne muscular dystrophy. The results of this research are encouraging for families affected by Duchenne muscular dystrophy, because if this could be successfully tested in clinical trials it could ultimately reduce the price of exon-skipping drugs. Research paves road to prognostic test for myotonic dystrophy Myotonic dystrophy type 1 (DM1) is caused by a mutation called a “triplet repeat expansion” which is an enlarged repetition of a short segment of DNA. Generally, healthy people have less than 35 repeats, but individuals with DM1 typically have more than 50 repeats. The lengthened repeated segment of DNA is unstable and the number of repeats increases over the lifetime of the individual. Different types of cell may also have different numbers of repeats – for instance muscle will generally have more repeats than blood cells and this has made it very difficult to predict accurately when an individual will develop the symptoms of DM1. The current diagnostic test for DM1 is a simple yes/no indicator. For many of the muscular dystrophies and related conditions, simply having a genetic test is enough to also be able to provide prognostic information. This has not been the case for DM1, where the unstable mutation makes the situation more complex. Due to these limitations, clinicians are advised not to give prognostic information based on the test, making it difficult for individuals and families to make informed lifestyle choices and plan for the future.

Prof Darren Monckton won an award for science communication at the National Conference

Now, Prof Monckton and colleagues at the University of Glasgow have investigated whether it was possible to accurately predict the age of onset from the number of repeats a person has.

Since the repeated segment of DNA expands as an individual gets older, Prof Monckton suggested that the number of repeats at birth might be a better predictor of the age when symptoms would start to appear. The team used cutting edge technology that can measure very small amounts of DNA, and complex computer modelling techniques to estimate how many repeats each individual had been born with. This repeat number had a major influence on the age at which symptoms started to appear. Although this was an exciting result, it was not fully able to explain the age at which symptoms started to appear; so the researchers also examined how unstable the repeated section of DNA was. If the repeated section expanded more quickly, then it must be more unstable. Further analysis of the DNA of people with DM1 revealed that individuals in whom the repeated section of DNA is more unstable showed symptoms at an earlier age. Importantly, they also showed that if someone has a tendency towards unstable repeats, this tendency can be passed on to their children. Although the techniques used in the study are not routinely used in diagnostic laboratories, they do share elements with standards tests. If the techniques could be implemented, this would allow clinicians to give more information to patients about how their condition will progress over time, which could allow families to plan for the future and make informed family planning choices. Protein degradation: a new drug target for Duchenne muscular dystrophy? In muscle cells, dystrophin forms part of a group of proteins called the dystrophin glycoprotein complex (DGC) which works to stabilise muscle structure by linking the internal skeleton of the muscle cell to structures outside the cell. When dystrophin is not in the group (for instance in Duchenne muscular dystrophy) the cell degrades the rest of the proteins. Now, scientists have shown in a mouse model that blocking this degradation can increase levels of the other proteins and help to stabilise the scaffold - leading to reduced muscle damage.

leading the way forward

10 In healthy muscle cells, the dystrophin protein hides a “signal” that tells the cell to degrade, or destroy, the DGC. The lack of dystrophin in Duchenne muscular dystrophy can uncover this “signal” and lead to the loss of the DGC resulting in a weaker structural scaffold inside the muscle cell. This means the muscle is more likely to be damaged when it contracts and eventually leads to the muscle weakness and wasting seen in Duchenne muscular dystrophy. A team of researchers led by Prof Steve Winder at the University of Sheffield has used an animal model of Duchenne muscular dystrophy to show that blocking the “signal” prevented the loss of the DGC in the absence of dystrophin. This led to an improvement in the muscle structure, and a reduction in muscle damage. When the researchers examined the proteins that were present in the DGC of the mice, they found a protein called plectin was doing the job that dystrophin would normally do. Plectin is a protein that plays a similar role to dystrophin, acting as a scaffold to give cells stability and structure. The researchers do not know why plectin, rather than one of the other scaffold proteins in the cell, was taking the place of dystrophin in the DGC and this will need further investigation. This research has identified a new target for potential drugs for Duchenne muscular dystrophy and, like potential drugs which aim to increase utrophin production, drugs that could target this pathway might have the potential to treat all people with Duchenne muscular dystrophy, regardless of their mutation. However, this work is at a very early stage. The techniques used to block the “signal” in mice could not be used in a clinical setting and so further research will be needed to identify candidate drugs which could specifically block the “signal” to degrade the DGC in the muscles of people with Duchenne muscular dystrophy.

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News in brief Reading through the nonsense Scientists from the University of California have found a drug-like molecule – called RTC13 – which can help cells to read through the stop signals created by nonsense mutations. Using a mouse model for Duchenne muscular dystrophy, the researchers found that injection of RTC13 directly into the muscle could restore dystrophin production. Injection into the abdomen restored dystrophin expression in a range of muscles including the legs, heart, and breathing muscle (diaphragm). The researchers also found that there was less muscle damage, and that mice treated with RTC13 performed better in strength tests than untreated mice. The researchers now intend to produce a form of RTC13 which can be taken orally. It will therefore be some time before the drug can enter clinical trials to test whether it can restore dystrophin production in the muscles of boys with Duchenne muscular dystrophy. Mitochondrial consultation underway Researchers at Newcastle University have developed new IVF-based techniques which may have the potential to prevent mitochondrial disease being passed from mother to child. For the techniques to develop further or move into clinical trials a change to the law is required, and the government has asked the Human Fertilisation and Embryology Authority to consult public opinion on the techniques. The consultation runs until December 7th 2012 and aims to bring together members of the public, clinicians, and scientists. To learn more about the consultation, please see ‘Mitochondrial myopathies - can we break the cycle on page 7’ or visit our website at www.muscular-dystrophy.org/research/news/5933_ mitochondrial_myopathy_consultation_launched_by_hfea. The Muscular Dystrophy Campaign will also be responding to the consultation. To make sure our response represents the views of our supporters, we will be running a discussion group in November. To find out more, please get in touch with the research team. Utrophin Update Oxford-based drug company Summit Corporation plc has issued a press release announcing preliminary results of their phase 1 clinical trial. The trial tested a drug (called SMT C1100) which may be able to treat Duchenne and Becker muscular dystrophy by increasing levels of a protein called utrophin. This may be able to compensate for the lack of dystrophin. During the trial, various doses of the drug were given to healthy volunteers, and researchers say the drug was safe and welltolerated at all doses. In 2010, a previous phase 1 trial of SMT C1100 found that only small amounts of the drug entered the bloodstream. Summit has now reformulated SMT C1100 to increase the amount that is taken into the blood. This phase 1 trial of the new formulation found higher levels of the drug in the bloodstream and researchers hope that the levels may be high enough to increase levels of utrophin in the muscles. A full analysis of the trial results will be available later in the year and Summit hopes the drug may now be tested in clinical trials involving people with Duchenne muscular dystrophy. Unlike other approaches such as exon skipping, SMT C1100 may have the potential to treat all boys with Duchenne or Becker muscular dystrophy, regardless of their mutation. The ability to treat so many boys means the results of the trial are encouraging.

Hello from Target MD! Gene therapy trial for LGMD 2C The results of a phase 1 clinical trial testing a gene therapy for limb girdle muscular dystrophy type 2C have shown that it is safe to use a harmless virus – called an adeno-associated virus (AAV) – to deliver a healthy copy of the g-sarcoglycan gene which is missing in LGMD2C. The virus was injected into a single muscle of the study participants. Participants who received the highest gene therapy dose and one patient from the middle-dose group had g-sarcoglycan present in the injected muscle. None of the participants suffered any serious side effects. This trial was primarily aimed at testing the safety of the therapy and so future trials will determine if there is a positive benefit for muscle strength or function. The researchers are now doing more pre-clinical work before starting a second trial that will be aimed at delivering the viral gene therapy to a whole limb. Eteplirsen update Sarepta Therapeutics (formerly AVI Biopharma) has announced, in a press release, encouraging interim results from their phase 2b clinical trial of the exon skipping drug eteplirsen in treating Duchenne muscular dystrophy. The new results show that the higher dose of eteplirsen slowed the decline in walking ability. After 36 weeks of treatment, those treated with the drug walked, on average, 69m further in six minutes than those given placebo and no serious side effects have been observed. However, the trial is small and included only 12 boys in total. This means the results must be treated with caution and that further, larger trials may be required. The trial participants are still being monitored though, and researchers will perform further walking tests and muscle biopsies after 48 weeks of treatment. If the results of these tests confirm those seen after 36 weeks, Sarepta Therapeutics say they will meet US drug regulators to discuss whether further, larger trials will be needed before the drug can be licensed. Ataluren update In a recent update about ataluren, PTC Therapeutics has announced that drug regulators in the USA were not convinced that the results of the ataluren phase 2b clinical trial were sufficiently robust to allow approval of the drug at the current time. The trial, which ended in 2009, showed that a high dose of ataluren had no beneficial effects. However, a lower dose showed encouraging results; increasing the distance boys could walk in six minutes and slowing the speed at which their walking performance declined. PTC Therapeutics now plans to organise another study in an attempt to confirm the results in the USA. Discussions with drug regulators in the EU are currently ongoing.

Links... Back issues of Target Research w: www.muscular-dystrophy.org/research/target_research_magazine Subscribe to our e-newsletter for monthly updates on research w: www.muscular-dystrophy.org/enewsletter

Greetings from all of us who put together Target MD, the lifestyle magazine for the Muscular Dystrophy Campaign. This edition features technology – a huge topic, which we could never do justice to in one single magazine! For some disabled people, technology offers a way into the world of work that might otherwise not be available; for others it offers the opportunity for entertainment and for yet others, technology literally keeps them alive. We also bring you news of five incredible Paralympians and their experiences of London 2012, as well as a regular update from the Wheelchair Football Association. Meet all of our Kite Award and President’s Award recipients for 2012 and read our latest campaigning, research and fundraising news. We’re keen to grow our subscriber base for Target MD and Target Research, so if you don’t already subscribe, please consider doing so? Your support really helps us to continue our vital work. Do let me know if you have any thoughts or comments about the magazine, or any ideas for future editions. We want to bring you news and stories you want to read. I’d love to hear from you.

Ruth Martin Editor, Target MD t: 020 7803 4836 e: r.martin@muscular-dystrophy.org tw: @RuthWriter

If you have any questions about this or any other research, please contact us: t: 020 7803 4813 e: research@muscular-dystrophy.org

Target MD is also available to read online: www.bit.ly/wTnEsn leading the way forward

Exercise training in neuromuscular disease How many times have you been told in the press, media and especially by healthcare professionals that exercise would be beneficial to your health? But is it safe if you have muscle disease? With little evidence of the benefits of exercise in people with muscular dystrophy or a related neuromuscular condition, advice in the past has often been confusing. The Muscular Dystrophy Campaign has recently funded two clinical studies which investigated the benefits of exercise for people with different neuromuscular conditions. Professor Mary Reilly and her colleagues at the MRC Centre for Neuromuscular Diseases and St George’s University of London/Kingston University carried out a study investigating the benefits of strength training in people with Charcot-Marie-Tooth disease. The study ran for two years and was based on previous research which showed that people with Charcot-Marie-Tooth disease tend to walk with high steps because of foot drop caused by muscle weakness in the ankle. This gait, with its compensatory movement leads to hip muscle fatigue. This, in turn causes people to become tired whilst walking and to stop regularly for rest. The strength-training study tested whether the hip muscles could be strengthened, and if so, whether stronger muscles would tire less and allow people to walk further. Thirty two people with Charcot-Marie-Tooth disease were recruited to the study and assigned to two groups. Both groups did 16 weeks of strength training and 16 weeks with no training, but one group trained first whilst the other rested first. The training aimed to strengthen the hip muscles with a home-based programme using ankle weights. A research physiotherapist showed participants the exercises at home, and established the correct number of weights for them. They then visited monthly to help people increase the load as they got stronger. The

participants attended the hospital three times where their hip strength, disease severity, activity levels, and fatigue were all measured. Clinicians also examined participants’ walking ability, by measuring the speed people walked, and the distance they could walk in six minutes. Participants were also asked to complete a questionnaire asking how well they thought they walked. Twenty eight of the thirty two participants completed both parts of the study and 93% of the exercises. According to the researchers, this was an excellent achievement and they were very grateful to all the patients for persevering with the exercises. The results showed that participants became significantly stronger in the left hip muscles after the 16 weeks of training, with no negative effects. This is an important message to disseminate because it is common for people with Charcot-Marie-Tooth disease to be told not to exercise for fear of worsening their condition. This study demonstrated that they can, in fact, increase their muscle strength safely. Overall, participants who were weaker at the start of the study showed the biggest improvements in strength, whilst people who were strong at the beginning didn’t change as dramatically. This is similar to people without neuromuscular diseases in that if someone is already very strong it is hard to make them much stronger. Think of an Olympic weight lifter – training every day and able to lift 200Kg. Even with extra training, he’s unlikely to lift much more weight. But if somebody who has never weight-lifted started the same training regime, then their performance would improve quickly.

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Although muscle strength was increased following the 16 weeks of training, no changes were seen in the distance or speed participants could walk, or in fatigue or activity levels. It is possible that the inclusion of walking training â&#x20AC;&#x201C; to change how somebody walks â&#x20AC;&#x201C; may have helped the increased strength to carry over into better function. However, this was beyond the scope of the trial which focussed on the effects of strength training. It is also possible that no changes were seen because of the relatively small number of people in the trial â&#x20AC;&#x201C; larger groups may be required to demonstrate small changes in these. The study also included people with different forms of Charcot-Marie-Tooth disease and of different activity levels, and it is possible that the variation in the condition and abilities of the participants may also have reduced the effects seen in the study. After the study the researchers followed the participants up by phone and nearly 40% felt the exercises were beneficial, whilst the rest felt unchanged. A quarter of the people they spoke to were still doing the exercises. Professor Mary M Reilly said: We are very grateful to all the patients who participated in the study and to the Muscular Dystrophy Campaign for funding the study. Following its success, we have applied for funding from the National Institute for Health Research to carry out a larger study of aerobic exercise in Charcot-Marie-Tooth disease.

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14 Researchers led by Prof. Doug Turnbull at the Mitochondrial Research Group at Newcastle University are focussing on trying to understand and develop treatments for patients with mitochondrial myopathies. They are currently using their knowledge to try and address the common questions associated with exercise in order to give patients the best possible advice. Describing the study, Prof Turnbull said: All of the patients who are participating in our study have what is known as mitochondrial myopathy. This is a common cause of inherited muscle disease and is caused when the batteries (called mitochondria) in the muscle cell fail. Patients with mitochondrial myopathies develop muscle weakness and excessive fatigue often due to mutations in mitochondrial DNA. At present there is no specific treatment for this form of muscle disease although exercise presents what may be an exciting way of helping our patients. This research aims at helping our patients not just in terms of muscle strength and endurance, but also because exercise increases the number of mitochondria. Exercise also stimulates the stem cells in muscle which can help by making new muscle fibres with healthy mitochondria.

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Currently our patients have given their time, immense dedication and even allowed us to do muscle biopsies to address some of the questions associated with exercise training and mitochondrial myopathy. The questions we were asked include: â&#x20AC;˘ How much exercise should I be doing? â&#x20AC;˘ What type of exercise is good for me? â&#x20AC;˘ Will it improve my quality of life? To address these questions patients undertook a 16-week resistive exercise training schedule where they were required to exercise 3 times per week. The weight bearing resistance exercise consisted of leg presses, leg extensions, hamstring curls and calf raises. Throughout the training process we took measurements of body composition and evaluated muscle using magnetic resonance imaging. We also performed tests on muscle biopsies and tested strength before and after training. We found that after 16 weeks of training patients had improved muscle strength, improved quality of life and improvements within their muscle biopsies. This is very encouraging for our patients. However, much more needs to be done to understand the mechanisms by which these improvements occur and determine the exact type and amount of training that would benefit our patients the most. We are very happy that we can offer clearer advice about a potential treatment for our patients who have mitochondrial myopathy. Our continuing studies are looking at the benefits of long term exercise in collaboration with the University of Texas. We are also exploring whether exercise would be good for other muscle diseases. We appreciate it is sometimes very difficult for patients with muscle disease to exercise and we are looking at ways to improve access to exercise for our patients. It is important to remember that it is always best to speak to your doctor before undertaking any form of exercise training. This is due to the fact that advice and type of training can vary considerably depending on the type of muscle disease you have and whether your heart or other tissues are involved.

Ask a Scientist The Muscular Dystrophy Campaign research team is always available to answer any questions about research. Questions we don’t know the answer to, we refer to our network of scientists and clinicians working in the field. In this article we posed some of the questions we have received recently to top researchers for further expert opinions.

Q. Instead of using pro-nuclear

transfer IVF to prevent mitochondrial disease being passed from mother to child, could paternal mitochondria be transplanted into the egg? Jenny Matthews

A. There are major technical and

biological barriers to using paternal – or the father’s – mitochondria to populate the egg. Whilst sperm contain a small number of mitochondria, the egg targets them for destruction around the time of fertilisation so these could not be used. Could we harvest mitochondria from other cell types such as skin cells from the father’s body? There are three main problems with this. Firstly, the cells of the body – called somatic cells – such as skin cells contain only around 1000-1500 mitochondria. An egg may contain up to 1 million copies. It would therefore be difficult to collect enough mitochondria from somatic cells to replace all those in the egg – it would be like putting a drop of water into a bucket. The second problem is that the mitochondrial DNA in our somatic cells acquires new mutations over

time. There is therefore a strong possibility that we would introduce new mutations into the egg. The third problem is that we would still be left with the mutations in the egg’s mitochondrial DNA. Unfortunately, using the mitochondria or mitochondrial DNA from the father’s cells does not provide a solution to the problem. Prof. Mary Herbert Professor of Reproductive Biology, Newcastle Fertility Centre, Newcastle University

Q. Our grandson who is 3 years and five months old has been diagnosed with a congenital myopathy called central core disease. Is it possible for you to advise us if there is any treatment for this condition? Anon

A. Central Core Disease (or CCD) is

one of the congenital myopathies, a group of neuromuscular conditions that usually present at birth or early in life. The names of congenital myopathies are based on characteristic changes that are seen when a small piece of muscle from a patient is

stained with special dyes and viewed under a microscope. As the name implies, the characteristic microscopic abnormalities in CCD are centrally located cores – areas with reduced staining, in the centre of the muscle fibres. CCD is most commonly caused by a mutation in the RYR1 gene, which carries the genetic blueprint for the skeletal muscle ryanodine receptor which has a fundamental role in muscle contraction. There is currently no cure for CCD but active management of the condition is very important. This would involve regular physiotherapy, gentle exercise and monitoring for potential complications. Regular physiotherapy and gentle exercise (such as swimming or horseriding) are important to maintain muscle function, to prevent joint contractures (tightening of the joints) and a curve of the spine, particularly in very weak children who are unable to engage in normal daily physical activities. Some individuals with CCD show a mild but definite improvement in muscle strength when treated with oral Salbutamol, a drug frequently used in the treatment of bronchial asthma but which is also given to patients with other neuromuscular conditions such as congenital myasthenic syndromes. Chewing, swallowing and breathing problems are probably less common than in other congenital myopathies, but will nevertheless have to be anticipated. Heart involvement has not been reported in children with CCD caused by mutations in the RYR1 gene. A specific complication of CCD is an increased risk of malignant hyperthermia, a rare but potentially life-threatening reaction to certain anaesthetics and muscle relaxants given during general anaesthesia; this is important to be aware of should the child require an operation – malignant hyperthermia is completely preventable, provided the anaesthetist is aware and certain drugs are avoided. Dr Heinz Jungbluth Senior Lecturer and Consultant in Paediatric Neurology at the Children’s Neurosciences Centre, St Thomas’ Hospital in London

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